Journal
CELLULAR SIGNALLING
Volume 20, Issue 10, Pages 1762-1768Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2008.06.002
Keywords
ERK1/2; MAP kinase pathway; MEK1; PAK1; Rac1; RhoA; WNK protein kinases; WNK2
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Funding
- Portuguese Fundacao para a Ciencia e Tecnologia [POCI/56294/04]
- Programa de Financiamento Plurianual do CIGMH [11180/02]
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WNK protein kinases form a kinase subfamily expressed in multi-cellular organisms and the human genome encodes four distinct WNK genes. Human WNK2 has been recently identified as a cell growth regulator that modulates activation of the ERK1/2 protein kinase and is epigenetically silenced in gliomas. Here we provide mechanistic insight into how WNK2 affects ERK activation. We found that WNK2 depletion decreased RhoA activation and promoted GTP-loading of Rac1, leading to stimulation of the Rac1-effector PAKI, which is the kinase responsible for subsequent phosphorylation of MEK1 at serine 298, thereby increasing MEK affinity towards ERK1/2. We propose that WNK2 controls a RhoA-mediated cross-talk mechanism that regulates the efficiency with which MEK1 can activate ERK1/2 upon growth factor stimulation. (C) 2008 Elsevier Inc. All rights reserved.
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